3beta-halo-delta5, 7-pregnadienes



United States Patent 3,074,976 3,8-HAL0-A -PREGNADIENES John A. Zderic,Palo Alto, Calif., and Otto Halpern and Jose Iriarte, Mexico City,Mexico, assignors, by mesne assignments, to Syntex Corporation, acorporation of Panama No Drawing. Filed Jan. 31, 1962, Ser. No. 170,267

18 Claims. (Cl. 260397.3)

The present invention relates to certain new cyclopentanophenanthrenederivatives and to a method for making the same.

More particularly the present invention refers to the novel 3p-halo-M-pregnadienes which may be further substituted at C-l7u by a hydroxy oracyloxy group and at 021 by a fluorine atom, a hydroxyl or an acyloxygroup.

The novel compounds of the present invention are represented by thefollowing formula:

CHrR

d" pg In the above formula X represents fluorine, chlorine or bromine; Rrepresents hydrogen, fluorine, hydroxy or acyloxy and R representshydrogen, hydroxy or an acyloxy group.

The acyloxy groups are derived from a hydrocarbon carboxylic acid ofless than 12 carbon atoms, including saturated or insaturated straightor branched chain, aliphatic, cyclic or cyclic aliphatic, optionallysubstituted with functional groups such as hydroxyl, acyloxy, alkoxy,amino or halogen. Typical ester groups are the formate, acetate,propionate, butyrate, enanthate, caproate, benzoate, hemisuccinate,aminoacetate, trimethylacetate, phenoxyacetate, phenylpropionate andfi-chloropropionate.

The novel compounds of the present invention are progestational agentswhich exhibit particularly anti-estrogenic, anti-androgenic andanti-gonadotrophic activities; they further posses anti-ovulatoryproperties.

The compounds object of our invention are obtained from the A-3B-hydroXy(acyloxy)pregnenes, introducing a double bond at C-7 bytreatment with N-bromosuccinimide, followed by dehydrobromination,saponifying the 3fl-acyloxy group when the starting material is an esterand replacing the hydroxyl group at 03 by a halogen atom.

The 3B-chloro, fluoro and brorno derivatives of A5- pregnen-ZO-one areobtained by the process illustrated by the following equation:

ons 2 1 cm 5 E? m a m g In the above formulas X represents chlorine,bromine or fluorine. 1

In practicing the process outlined above, an ester of A-pregnen-3fl-ol-20-one, preferably the acetate (1) is refluxed for a.short period of time with 1.2 molar equivalents of N-bromosuccinimidein the presence of a suit.- able organic solvent and stronglyilluminated with artificial light, to produce the corresponding 7-bromoderivative (II). The reaction is preferably carried'out in carbontetrachloride or hexane as solvent although some other inert solventsmay also be used.

The 7-bromo compounds thus produced are then dehydrobrominated byrefluxing the same with a tertiary amine, such as collidine,2,4-lutidine, dimethyl aniline, pyridine or the like, for a period oftime of, the order of 1 to 2 hours, thus producing A-pregnadien-318-01-20-one acetate or any other ester (III). Thedehydrobromination may be alternatively effected by refluxing the 7-bromo compounds with calcium carbonate in dimethyl formamide or dimethylacetamide, for a short period of time, preferably for 15 to 30 minutes.

Upon saponification with potassium hydroxide in methanol solution, in aconventional manner, there is produced A -pregnadien-3fl-ol-ZO-one (IV).

In order to obtain the 3,8-chloro-A -pregnadien-3/3-ol- 20-one (V;X=Cl), the preceding compound is treated with phosphorus pentachloridein an inert solvent, preferably in an aromatic hydrocarbon such asbenzene, xylene or toluene, at reflux temperature and for a period oftime of the order of 30 minutes to 3 hours, preferably during one hour.When phosphorus pentabromide is used instead of phosphoruspentachloride, there is obtained the corresponding 3B-bromo-A-pregnadien-20-one (V; X=Br).

By treatment of A -pregnadien-3B-ol-2O-one with anhydrous hydrogenfluoride in mixture with tetrahydrofuran-methylene chloride, there isproduced the corresponding 3fl-fluoro compound (V; X=F). The reaction ispreferably conducted at low temperature between and 0 C. and during 18to 24 hours.

The BB-halo-17arhydroxy(acyloxy)-pregnadienes are obtained by convertingthe diesters of A -pregnene-3fi,l7adiol-ZO-one, preferably thediacetate, into the corresponding 7-bromo derivative by treatment withN-brornosuccinimide in carbon tetrachloride solution anddehydrobrominating with collidine or calcium carbonate in dimethylformamide to produce A -pregnediene-3fl,17a-diol-2O one diacetate, whichis selectively saponified at C-3 by treatment with potassium hydroxidein methanol solution at room temperature to give the corresponding17-monoacetate. Upon treatment of thiscompound with phosphoruspentachloride, phosphorus pentabromide or anhydrous hydrogen fluoride,in the same manner as in the case of the compounds not substituted atC-17a, there are produced the acetate of 3fl-chloro-A-pregnadien-17aol--one, the acetate of 3fi-bromo-A-pregnadien-17aol-20-0ne and the acetate of 3/8-fiuoro-A -pregnadien-17a-ol-20-one, which are then saponified with dilute potassium hydroxidemethanolic solution and at reflux temperature to give the correspondingfree compounds. Reesterification of these with acid anhydrides orchlorides of less than 12 carbon atoms in benzene solution and in thepresence of p-toluenesulfonic acid give rise to other esters of3p-chloro, 3p-bromo and 3 p-fluoro-A -pregnadien-17aol-20-one. V

In a similar manner, starting from the 3,21-diacetate of A-pregnene-3fl,21-dio1-20-one, there is produced the correspondingdiacetate of A -pregnadiene-3/8,2'l dio1-20- one via the 7-bromoderivative, which is then saponified by treatment with potassiumhydroxide or potassium carbonate at room temperature, to afiord A-pregnadien-3fi- 2ldiol-20-one. The above compound is then selectivelyacetylated at C-2l by treatment with 1.1 molar equivalents r of aceticanhydride in pyridine solution and at 0 C. overnight. The resultingZI-monoacetate is then reacted with phosphorus pentachloride or.phosphorus pentabromide'in benzene solution or with anhydrous hydrogenfluoride in mixture with tetrahydrofuranmethylene chloride,rthusproducing the acetates of 3B-ch1oro, 3,8-bromo and 3fl-fluQm-A-pregnadien-Z1-ol-2O-one, which may be'saponified with dilute potassiumhydroxide or potas-' sium carbonate in methanol solution and at lowtemperature, and optionally reesterified by treatment with acidanhydrides'orjchlorides of less than 12 carbon atoms and in the presenceof pyridine.

The 318-halo derivatives of A -pregnadiene-17,21-di01 20-one areobtained by the method illustrated by the following equation:

O-GH:

' In the above formulas X has the same meaning as pre 7 viously setforth, R and R represent hydrogen or an acyl group of less than 12carbon atoms.

In practicing the process set forth above in the 17,20;20,2l-bismethylenedioxy derivative of A -pregnene-3B,17a,2l-triol-20-one (VI), there is introduced a double bond at 07 bybromination with N-bromosuccinimide followed by dehydrobromination aspreviously described, and the resulting 17,20;2O,21-bismethylenedioxy-A-pregnadicn-Bfi-ol (VII) is then reacted With phosphorus pentachloride,phosphorus pentabromide or hydrogen fluoride thus producing thecorresponding 3,8-halo compound (VIII). The bismethylenedioxy group ishydrolyzed by treatment with formic acid to give 3fl-ch1oro-Apregnadiene-l7a,2l diol-ZO-one, 3B bromoA-pregnadiene-l7a,2l-diol-20-one and 3fi-fluoro-A -pregnadien-17a,21-dlO1- -20-0I16 (IX; R and R =hydrogen).

Upon esterification of these compounds with acid anhydn'des or chloridesof the type previously mentioned, in pyridine solution, there areproduced the corresponding ZI-monoesters (IX; R =acyl, R =hydrogen).When the esterification is effected in benzene solution and in thepresence of p-toluenesulfonic acid, there are produced the17,21-diesters (IX; R and R3=acyl).

The 3,8-halo-21-fluoro-A -pregnadien-20-one derivatives are obtianed byconverting an acylate of A -pregnadien-3fl-ol-20-one (III), preferablythe acetate, into the 21-iodo compound (X), by treatment with iodine andcalcium oxide in mixture of tetrahydrofuran-methanol. Substitution ofthe iodine for a fluorine atom, by treatment with silver fluoride inaqueous acetonitrile afiords the 21 fluoro-A -pregnadien-3fi-ol-2O-oneacetate, which is then saponified and the free compound thus obtained(X1) is treated with phosphorus pentachloride, phosphorus pentabromideor hydrogen fluoride, thus producing 3fl-chloro- 2l-fluoro-A?-pregnadien-20-one, 3 ,8 bromo 21 fluoro- A -pregnadien-20-one and35,2l-difiuoro-A i -pregnadien- ZQ-one respectively (XII).

The above described method is illustrated by the following sequence ofreactions:

CH CHzI CHzF % 5 r6 no In the above formulas X has the same meaning aspreviously set forth.

The 3fi-halo-2l-fluoro-A -pregnadien-17a-ol-20-one derivatives, as Wellas the corresponding esters are obtained by the same sequence ofreactions, but starting with a 3,17-diester of A-pregnadiene-3fl,17a-dio1-2O-one. Alternatively these compounds may alsobe obtained from the acetate of 17,20;20,21-bismethylenedioxy-A-pregnadien-3B-ol, which is hydrolyzed with 60% formic acid to give A-pregnadiene-3/3,17u,2l-triol-20 one 3 acetate.

The latter compound is then converted into the correspondingS-acetate-ZI-tosylate, and the tosyloxy group is replaced by a fluorineatom by treatment with sodium iodide, followed by reaction with silverfluoride in acetonitrile. The 21-fluoro-A -pregnadiene-3B,17ot-dio1-20-one-3-acetate thus obtained is then esterified at C-17 by treatment withacid anhydrides or chlorides in benzene solution and in the presence ofp-toluenesulfonic acid, the acetate group at G3 is selectivelysaponified and finally substituted by a fluorine, chlorine or bromineatom, as described previously.

The following examples serve to illustrate but are not intended to limitthe scope of the present invention:

Example I From a solution of 10 g. of A -pregnen-3fi-ol-20-one acetatein 100 cc. of carbon tetrachloride, there were distilled 20 cc. ofsolvent to remove moisture by azeotropic distillation. 5 .9 g. ofN-bromosuccinimide was then added (1.2 molar equivalents) and themixture was heated to boiling by the use of an electric lamp, which atthe same time illuminated strongly the reaction mixture. After 5 minutesof reflux the mixture was cooled and filtered to remove the succinimideformed during the reaction. The filtrate was evaporated to dryness underreduced pressure avoiding heat, thus giving the 7-bromo-A-pregnen-3fi-ol- ZO-one-acetate, which was used for the next stepWithout further purification.

The above crude compound was refluxed with 100 cc. of 'y-collidine for 2hours under an atmosphere of nitrogen. It was then cooled, poured into a2 N solution of hydrochloric acid, extracted with ethyl acetate and theorganic solution washed to neutral, dried over anhydrous sodium sulfateand evaporated to dryness to give the crude Apregnadien-ZB-ol-20-one-acetate. This crude product was suspended in 250cc. of 1% methanolic potassium hydroxide solution and stirred for 3hours at 5 C. under .an atmosphere of nitrogen. It was then diluted withwater,

and the formed precipitate collected by filtration. Aftercrystallization from benzene-alcohol, there was obtained A-pregnadien-35-ol-2O-one.

To a solution of g. of A -pregnadien-3fi-ol-ZO-one in 100 cc. ofbenzene, there were added 5 g. of phosphorus pentachloride and theresulting mixture was refluxed for 1 hour in the absence of moisture. Itwas then cooled and poured into water; the benzene layer was washed withwater several times, dried over anhydrous sodium sulfate andevaporatedto dryness. Crystallization of the residue from acetone-hexane yielded3,8-chloro-A -pregnadien- 20-one.

Example 11 In accordance with the method of bromination described in thepreceding Example, 5 g. of A -pregnene- 3,8,2l-diol-ZO-one-diacetate wastreated with N-bromosuccinimide, thus giving 7-br0mo-A-pregnene-3B,2l-diol-20- one-diacetate.

A solution of the above bromo compound in 40 cc. of colddimethylformamide was added to a suspension of 5 g. of finely dividedcalcium carbonate in 75 cc. of refluxing dimethylformamide. The mixturewas refluxed for 30 minutes further, cooled and filtered. The filtratewas diluted with water and extracted with ethyl acetate. The extract waswashed with dilute hydrochloric acid, water, aqueous sodium bicarbonatesolution and water, then dried over anhydrous sodium sulfate andevaporated to dryness. Recrystallization of the residue from methylenechloridemethanol gave A -pregnadiene-3B,2l-diol-2O-one diacetate.

A solution of 2 g. of the above compound in 50 cc. of methanol wastreated with a cc. of a 4% aqueous solution of potassium hydroxide; thereaction mixture was stirred for 2 hours under an atmosphere of nitrogenat room temperature; the mixture was neutralized with acetic acid andthe methanol distilled under reduced pressure.

The residue was triturated with water and the solid collected, washedwith water, dried and recrystallized from [ethyl acetate-methanol, thusproducing A -pregnadiene- 313,2l-diol-20-one.

A solution of 1 g. of the latter compound in 5 cc. of pyridine wastreated with 0.34 g. of acetic anhydride (1.1 equivalents) and themixture kept at 0 C. for 18 hours. It was then diluted with water,extracted with methylene chloride and the organic extract washed withdilute hydrochloric acid and water to neutral, dried over anhydroussodium sulfate and evaporated to dryness. Crystallization fromacetone-hexane gave A -pregnadi ene-3fi,21-diol-20-one-2l-monoacetate.

500 mg. of the above compound were treated with phosphoruspentachloride, in accordance with the method rescribed in Example 1,thus giving the acetate of 35- chloro-A -pregnadien-2l-ol-20-one.

Example 111 In accordance with the bromination method of Example I, butusing hexane instead of carbon tetrachloride as solvent, 10. g. of thediacetate of A -pregneue-3p,17a-diol-20- one were converted into the7-bromo derivative, which upon dehydrobromination with calcium carbonatein dimethylformamide gave A -PIgl1adl6l1-3,B,17OL-dlO1-20-one-diacetate.

A solution of 2 g. of the above compound in 50 cc. of methanol wastreated with 400 mg. of potassium hydroxide in 2 cc. of water, and thereaction mixture kept at room temperature for one hour. It was thenneutralized with acetic acid, concentrated to /3 its volume undervacuurn, poured into Water and the formed precipitate collected byfiltration. There was thus obtained the 17-acetate of A -pregnadiene-3B, l7oc-diol-20-one.

Upon treatment of the above compound with phosphorus pentachloride inbenzene solution, by following the method of Example I, there wasobtained 3B-chloro-A pregnadien-l7a-ol-20-one-acetate.

Example IV In accordance with the method described in Example I, 5 g. of17 ,20;20,21-bisrnethylenedioxy-A -pregnen-3 3-01 obtained by treatmentof A -pregnene-3B,17a,21-triol-20- one with formaldehyde in the presenceof hydrochloric acid by following the method described in U.S. PatentNo. 2,888,456, were converted into the corresponding 7 -bromoderivative, which in turn was dehydrobrominated with collidine to give17,20;2O,21-bismethylenedioxy-A pregnadien-BB-ol. The latter compoundwas then treated with phosphorus pentachloride, thus giving3,6-chlor0-l7, 2O;2O,21-bismethylenedioxy-A -pregnadiene.

A mixture of l g. of the preceding compound and 20 cc. of 60% formicacid was heated on the steam bath for 1 hour; it was then cooled,diluted with water and the formed precipitate collected by filtration.Recrystallization from acetone-ether gave 3 8-chloro-A-pregnadienel7a,21-diol-20-one.

A mixture of 1 g. of the latter compound, 4 cc. of pyridine and 2 cc. ofacetic anhydride was kept at room temperature overnight, poured into iceWater, the formed precipitate was filtered, washed with Water and dried.Crystallization from acetone-hexane gave BB-chloro-Apregnadiene-l7a,21-diol-20-one-21-acetate.

By the same method of esterification, but using propionic, caproic andundecenoic anhydrides as esterifying agents, there were obtained thecorresponding 21-esters of 3 6-chloro-A -pregnadiene-:,2l-diol-20-one.

Example V chloride 2l-triol-20-one-3-acetate.

A solution of 3.4 g. of the above compound in 20 cc. of a mixturechloroform-pyridine (9:1) was cooled to C. and-mixed with 1.4 g. oftosyl chloride which was added in small portions. The reaction mixturewas kept for 14 hours at 0 C. and then it was washed with dilutehydrochlorieacid, water and sodium bicarbonate 'solution and thechloroform was evaporated under vacuum. The residue, consisting of thecrude 21-tosylate-3-acetat e of 'A -pregnadiene-3B,17a,21-triol-20-onewas dissolved in 20 cc. of acetone and treated at room temperature and.

under stirring with 4 g. of sodium iodide. After decolorizing themixture by the addition of sodium thiosulfate solution the productwasprecipitated by the addition of water and the crystalline 2l-iododerivative was collected by filtration. The crude product was dried invacu um, dissolved in 20 cc. of acetonitrile and treated dropwise with1.4g. of silver fluoride dissolved in 3 cc. of water. After a shorttime, silver iodide started to separate leaving the21-fiuoro-pregnadiene derivative'in solution. The mixture was kept for24 hours at room temperature andfiltered. Concentration of the filtrateunder vacuum gave a crude product which after crystallization 'fr'ommethanol-acetone yielded the pure 21-fluoro compound, namely 21-fluoro-A-pregnadiene-3p,17a-diol-20- one-3-acetate.

To a solution of 2 g. of the above 21-fluoro compound in 40 cc. ofanhydrous benzene, there were added 400 mg. of ptoluenesulfonic acid and4 cc. of a propionic anhydride and the mixture was allowed to stand for24 hours at room temperature, poured into ice and water, and theresulting mixture stirred to effect hydrolysis of the excess anhydride.The benzene layer was separated and Washed with sodium carbonatesolution and water. Drying, evaporation and crystallization of theresidue from ether hexane produced 21-fluoro-A-pregnadiene-313,17a-di0l- 20-one-3-acetate-17-propionate.

The above compound was selectively hydrolyzed at C-3,

in accordance with the saponification method described in Example III,thus producing 21-fluoro-A -pregnadiene- 33-,17m-diol-20-one-17-propionate. Upon treatment of the latter compoundwith phosphorus pentachloride", in accordance with the method of ExampleI, there was obtained 3 -chloro-2l-fluoro-A -pregnadien- 1l7a-ol-20-onepropionate.

Example VI To a solution of 1 g. of A -pregnadien-3fl-ol-20-one in 20cc. of benzene was added 1 g. of phosphorus pentabromide and theresulting mixture was refluxed for 1 hour in'the absence of moisture. Itwas then cooled, poured into water; the benzene layer was washed withwater sevof p-toluenesulfonic acid was kept at room temperature for 1hour; it was then diluted withwater, stirred for 30 minutesatroomtemperature to hydrolyze the excess of anhydride, and extracted severaltimes with methylene The organic extract was washed with 10% sodiumcarbonate solution and water to neutral, dried over 20cc..ofacetic'acid, 10 cc. of acetic anhydride and 1 g. p

anhydrous sodium sulfate and evaporated to dryness. Recrystallizationfrom acetone-hexane gave the 3,17-diacetate of 2 1 -fluoro-A-pregnadiene-3 ,B, 1 7a-diol-2O-one'.

The above compound was selectively hydrolyzed at O3, in accordance withthe saponification method of Example III, and the resulting 21-fiuoro-A-pregnadiene-3fl,17adiol-20-one-17-acetate treated with phosphoruspentabromide, by applying the method described in the preceding example,thus producing 3fl-bromo-21-fluoro-A -pregnadien-17a-ol-20-one-acetate.

Example VIII To a mixture of 16.7 g. of anhydrous hydrofluoric acid and28.1 g. of anhydrous tetrahydrofuran, previously cooled to C. in a DryIce-acetone bath, there was carefully added a suspension of 2 g. of A-pregnadien- 3/3-ol-20-one in 30 cc. of methylene chloride. Theresulting mixture was stirred during 1 hour at -80 C. and kept standingat 0 C. overnight. It was then poured into ice water and neutralizedwith sodium carbonate. The organic layer was separated and the aqueouslayer extracted several times with methylene chloride. The combinedorganic extracts were washed with water to neutral, dried over anhydroussodium sulfate and evaporated to dryness under reduced pressure. Theresidue was chromatographed on g. of washed alumina. The fractionseluted with hexane-benzene (80:20) gave the desired 3p-fiuoro-n-pregnadien-20-one. g

Example IX By applying the fluorination method described in thepreceding example, A '7-pregnadiene-3B,17a-diol-20-one- 17-acetate,intermediate of Example III, was converted into 3B-fluor0-A-pregnadieml7a-ol-20-one-acetate.

A mixture of 2 g. of the latter compound and 60 cc. of 0.5% methanolicpotassium hydroxide solution was refluxed for 2 hours under nitrogenatmosphere. The resulting solution was then neutralized with aceticacid, coninto ice and water, and the resulting mixture stirred for 15minutes to eifect hydrolysis of the excess anhydride. The 'benzene layerwas separated and washed with 10% sodium carbonate solution and water.Drying, evaporation and crystallization of the residue from ether-hexaneproduced 3,6-fluoro-A-pregnadien-17a-ol-20-one-17-cyclopentylpropionate.

In a similar manner, but using caproic and butyric anhydride asesterifying agents, there were produced the 'caporate and butyrate of 3fl-fluoro-N -pregnadien-l701-01- 20-one.

Example X In accordance with the method of fluoriuation described inExample VIII, 2 g. of 17,20;20,21-bismethylenedioxy- A-pregnadien-3p-ol, intermediate of Example IV, were treated withanhydrous hydrogen fluoride in a mixture of methylenechloride-tetrahydrofuran, thus giving lift-fluorov17,20;20,21-bismethylenedioxy-A -pregnadiene.

The bismethylenedioxy group was then hydrolyzed with 60% formic acid, byfollowing the method described in Example IV to produce 3fl-fluoro-A-pregnadiene-17a,21- diol-20-0ne.

Upon treatment of the above compound with acetic acid in pyridinesolution, in a conventional manner, there 'was produced 3 fi-fluoro-A i-pregnadiene-17a,21-diol-20- one-Zl-monoacetate.

9 Example XI A mixture of 1 g. of 3,8-chloro-A -pregnadiene-170;,21-diol-ZO-one obtained as described in Example IV, 20 cc. of benzene, 4cc. of acetic anhydride and 200 mg. of p-toluenesulfonic acid was keptat room temperature for 24 hours. It was then poured into water andstirred for 15 minutes to hydrolyze the excess of anhydride. The benzenelayer was separated and washed with sodium carbonate solution and waterto neutral, dried over anhydrous sodium sulfate and evaporated todryness. Crystaliization from acetone-hexane gave 3/3-chloro-A-pregnadiene-17a,21-diol-20-one-diacetate.

By the same method, 3B-fiuoro-A -pregnadiene-170:,21- diol-ZO-one wasconverted into its diacetate.

Example XII A cooled solution of 4 g. of A -pregnadien-3p-ol-20-one-acetate obtained as described in Example I, in 30 cc. oftetrahydrofuran and 18 cc. of methanol was treated under continuousstirring with 6 g. of pure calcium oxide, in small portions, and thenwith 6 g. of iodine. The stirring was continued at room temperatureuntil the solution turned pale yellow. The mixture was poured into icewater containing 18 cc. of acetic acid and 2 g. of sodium thiosulfate.After stirring for minutes the solution was decanted and the precipitatewas collected by filtration, thus giving 21-iodo-A"-pregnadien-3p-ol-20-oneacetate.

The above compound was then treated With silver fluoride in aqueousacetonitrile, by following the method described in Example V, to produce2l-fiuoro-A -pregnadien-3fi-ol-Ztl-one-acetate. Upon saponification ofthe latter compound in accordance with the method of Example III, therewas obtained 2l-fluoro-A pregnadien- 3B-ol-20-one, which was then heatedwith phosphorus pentachloride in benzene solution, thus affording 3B-chloro-21-fluoro-A -pregnadien--one.

Example X111 1 g. of 21-fluoro-A -pregnadien-3B-ol-2O-one was treatedwith anhydrous hydrofluoric acid in mixture withtetrahydrofuranmethylene chloride, by following the method of ExampleVIII to produce 35,21-difiuoro-A -pregnadien-20-one.

Example XIV By following the saponification method described in ExampleIX, the acetate of 3B-chloroA -pregnadien-17aol-20-one was refluxed for2 hours with 0.5% methanolic potassium hydroxide solution to give thecorresponding 10 free compound which was reesterified with caproicanhydride in benzene solution and in the presence of ptoluenesulfonicacid, thus producing 3fl-chloro-A -pregnadien-17ot-ol-20-one caproate.

We claim: 1. A compound of the following formula:

CH2R

\fi' no? I consisting of hydrogen, hydroxy and acyloxy of less than 12carbon atoms.

. 3[i-chloro-A -pregnadien-20-one. 3fi-bromo-A -pregnadien-20-one.3B-iluoro-A -pregnadien-20-one. 3B-ch1oro-A -pregnadien-17a-ol-20-one.3B-fiuoro-A -pregnadien-17a-o1-20-one. 3 ,B-chloro-A-"-pregnadien-17a,21-diol-20-one.

3B-fluoroh-pregnadiene-17a,21-diol-20-one. 3 [3-cl1loro-2 1-fiuoro-A-pregnadien-20-one.

35,2l-difluoro-A -pregnadien-ZO-One. 3,8-chloro-Apregnadien-21-ol-2O-one. The acetate of 3fl-chloro-A-pregnadien-Z1-ol-20- u ss-se one.

one.

one.

15. The propionate of 3,8-chloro-21-fluoro-A -pregnadien-17u-ol-20-one.

16. The 21-caproate of 35-chloro-A -pregnadiene-Uu, 21-diol-20-one.

17. The cyclopentylpropionate of 3fi-fluoro-A -pregnadien-17u-ol-20-one.

18. The 17,21-diacetate of 3 8-fiuoro-A -pregnediene- :,2l-di0l-20-0I16.

The acetate of 3ebromo-A -pregnadien-Z1-o1-20- The acetate of 35-bromo-A-pregnadien-17oc-ol-20 No references cited.

1. A COMPOUND OF THE FOLLOWING FORMULA: